Recent studies have suggested a link between some cases of restenosis and the herpesvirus, human cytomegalovirus (HCMV). A closer examination revealed that this relationship correlated with HCMV immediate early (IE) gene expression in restenosis lesions and the stabilization and inactivation of the p53 tumor suppressor. These observations suggest a hypothesis that restenosis is caused by p53 inactivation by HCMV infection or other events that down regulate p53 activity. We propose to further examine the relationships between the HCMV IE gene products, p53, and cell proliferation control. We will examine whether HCMV IE gene expression contributes to the overproliferation of smooth muscle cells observed in restenosis. We will address these issues by employing a powerful approach, which utilizes replication, defective, recombinant adenoviruses to transiently introduce and express genes of interest. By using this approach, we propose: (1) to determine the extent to which HCMV IE gene expression affects cell cycle regulation; (2) to determine the biochemical mechanisms by which HCMV IE gene expression affects cell cycle - alteration of RB and p53 functions; and (3) to examine the effects of HCMV IE gene expression on early passage arterial smooth muscle cells. Together, these experiments will clarify the role of HCMV infection in restenosis.